嵌合抗原受体（CAR）T细胞免疫疗法对于血液系统肿瘤非常有效。然而，由于肿瘤的变异性、低抗原特异性和CAR-T细胞的不可持续存活，它们在实体肿瘤治疗方面的应用受到限制。本研究使用慢病毒转导构建了一种新型的CAR-T细胞，其中靶向B7-H3，并结合带有STAT3和STAT5相关激活基序的4-1BB共刺激分子。肿瘤相关抗原B7-H3及其的单链抗体赋予CAR-T细胞肿瘤特异性定位能力。此外，trIL2RB和YRHQ基序的整合以抗原依赖的方式刺激STAT5和STAT3，通过激活JAK-STAT信号通路引发CAR-T细胞的显著增殖和存活。此外，BB-trIL2RB-z(YRHQ) CAR-T细胞中的较低分化T细胞比例增加。此外，BB-trIL2RB-z(YRHQ)在低剂量下有效抑制了卵巢癌（OC）和三阴性乳腺癌（TNBC）的体内生长，而没有高血清水平的炎性细胞因子和器官毒性。因此，我们的研究提出了构建优质多能CAR-T细胞的组合元素，为治疗难治性实体肿瘤提供了有效的策略。版权所有© 2023. Elsevier B.V.发表。

Chimeric antigen receptor (CAR)-T cell immunotherapy is highly effective against hematological neoplasms. However, owing to tumor variability, low antigen specificity, and impermanent viability of CAR-T cells, their use in the treatment of solid tumors is limited. Here, a novel CAR-T cell targeting B7-H3 and incorporating a 4-1BB costimulatory molecule with STAT3-and STAT5-related activation motifs was constructed using lentivirus transduction. B7-H3, a tumor-associated antigen, and its scFv antibody endowed CAR-T cells with tumor-specific targeting capabilities. Moreover, the integration of the trIL2RB and YRHQ motifs stimulated STAT5 and STAT3 in an antigen-dependent manner, inducing a remarkable increase in the proliferation and survival of CAR-T cells via the activation of the JAK-STAT signaling pathway. Besides, the proportion of less-differentiated T cells increased among BB-trIL2RB-z(YRHQ) CAR-T cells. Moreover, BB-trIL2RB-z(YRHQ) effectively inhibited ovarian cancer (OC) and triple-negative breast cancer (TNBC) in vivo at low doses, without high serum levels of inflammatory cytokines and organ toxicity. Therefore, our study proposes a combination of elements for the construction of superior pluripotent CAR-T cells to provide an effective strategy for the treatment of intractable solid tumors.Copyright © 2023. Published by Elsevier B.V.